Varney Scott D, Erkes Dan A, Mersky Glenn L, Mustafa Manal U, Chua Vivian, Chervoneva Inna, Purwin Timothy J, Alnemri Emad, Aplin Andrew E
Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.
Mol Cancer Res. 2025 Apr 1;23(4):350-362. doi: 10.1158/1541-7786.MCR-24-0508.
Few treatment options are available for patients with metastatic uveal melanoma. Although the bispecific tebentafusp is FDA approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of uveal melanoma. Treatment options that improve the recognition of uveal melanoma by the immune system may be key to reducing disease burden. We investigated whether uveal melanoma has the ability to undergo pyroptosis, a form of immunogenic cell death. Publicly available patient data and cell line analysis showed that uveal melanoma expressed the machinery needed for pyroptosis, including gasdermins D and E (GSDMD and E), caspases 1, 3, 4, and 8, and ninjurin-1. We induced cleavage of GSDMs in uveal melanoma cell lines treated with metabolic inhibitors. In particular, the carnitine palmitoyltransferase 1 (CPT1) inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage, and the release of HMGB1 and IL-1β, indicating that the observed cleavage of GSDMs led to pyroptosis. Importantly, a gene signature reflecting CPT1A activity correlated with poor prognosis in patients with uveal melanoma and knockdown of CPT1A also induced pyroptosis. Etomoxir-induced pyroptosis was dependent on GSDME but not on GSDMD, and a pyroptosis gene signature correlated with immune infiltration and improved response to immune checkpoint blockade in a set of patients with uveal melanoma. Together, these data show that metabolic inhibitors can induce pyroptosis in uveal melanoma cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in patients with metastatic uveal melanoma. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.
对于转移性葡萄膜黑色素瘤患者，可用的治疗选择很少。尽管双特异性tebentafusp已获美国食品药品监督管理局（FDA）批准，但免疫疗法在很大程度上已失败，这可能是由于葡萄膜黑色素瘤免疫原性较差。能够提高免疫系统对葡萄膜黑色素瘤识别能力的治疗选择可能是减轻疾病负担的关键。我们研究了葡萄膜黑色素瘤是否有能力发生焦亡，焦亡是一种免疫原性细胞死亡形式。公开可用的患者数据和细胞系分析表明，葡萄膜黑色素瘤表达了焦亡所需的机制，包括gasdermin D和E（GSDMD和E）、半胱天冬酶1、3、4和8以及神经损伤诱导因子-1。我们在用代谢抑制剂处理的葡萄膜黑色素瘤细胞系中诱导了GSDMs的切割。特别是，肉碱棕榈酰转移酶1（CPT1）抑制剂依托莫西诱导了碘化丙啶摄取、半胱天冬酶3切割以及HMGB1和IL-1β的释放，表明观察到的GSDMs切割导致了焦亡。重要的是，反映CPT1A活性的基因特征与葡萄膜黑色素瘤患者的不良预后相关，并且CPT1A的敲低也诱导了焦亡。依托莫西诱导的焦亡依赖于GSDME而不是GSDMD，并且在一组葡萄膜黑色素瘤患者中，焦亡基因特征与免疫浸润相关，并改善了对免疫检查点阻断的反应。总之，这些数据表明代谢抑制剂可诱导葡萄膜黑色素瘤细胞系发生焦亡，这可能为转移性葡萄膜黑色素瘤患者增强炎症介导的免疫靶向提供一种方法。启示：通过代谢抑制诱导焦亡可能会改变肿瘤免疫微环境，并提高葡萄膜黑色素瘤免疫治疗的疗效。
